PROJECTSUMMARY/ABSTRACT Synthetic cathinones, often marketed as bath salts, are dangerous psychoactive drugs of abuse which are perceived by users as a safe, legal high. Synthetic cathinones, like 3,4-methylenedioxypyrovalerone (MDPV), exhibit stimulant effects similar to cocaine and amphetamines;? however, secondary effects can lead to psychosis, cardiovascular toxicity, and death. MDPV is available to drug users as a racemic mixture, but the central nervous system and cardiovascular effects are primarily attributed to the (S)-enantiomer. While there arecurrentlynovaccinesapprovedfortreatingsubstanceusedisordersinhumans,severalvaccinestoprotect againstmedicallydangerousabusedsubstancesareinclinicaltrials.Thehypothesisforthisprojectisthat an(S)-MDPV-conjugatevaccinecanmitigateadverseeffectsofMDPV-likedrugsofabuse.InAim1,an (R,S)-MDPV and (S)-MDPV vaccine will be investigated for optimal immunochemical and pharmacological characteristics in male and female Sprague Dawley rats. Following immunization, rats will be administered MDPV;? and serum concentrations of MDPV will be determined. Serum will also be characterized for immune response, specificity, and selectivity for (S)-MDPV-like cathinones. In Aim 2, the selected MDPV vaccine will be assessed in male and female rats for effectiveness and safety following escalation doses of MDPV using translationallyimportantbehavioralandcardiovascularparameters.Fordeterminingvaccine-inducedchanges instimulantactivity,ratlocomotoractivitywillbemeasuredafteradministrationofMDPVtoquantifyhorizontal and vertical movement. To determine changes in cardiovascular parameters, rats will be implanted with devices that record heart rate, blood pressure, and temperature and challenged with MDPV. In Aim 3, the vaccinewillbetestedinself-administrationstudiestoassesstheabilitytoalterthereinforcingeffectsofMDPV andtoevaluatethesafetyofthevaccine. Resultsfromthesestudiescouldsignificantlyimprovethedesignof targetedimmunotherapyforthetreatmentofsubstanceusedisorderscausedbyracemicmixtures.Theoverall proposal provides advanced training for a translational scientist who is capable of integrating knowledge from analyticalchemistry,pharmacokinetics,behavioralsciences,andbiological-basedmedicationstomaximizethe probabilityofimportantdiscoveriesforaddressingtreatmentofcathinoneusedisorders.